1-oxygenated-6-acyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocines

ABSTRACT

1,2,3,4,5,6-Hexahydro-2,6-methano-3-benzazocines characterized by the presence of an alkanoyl or benzoyl group in the 6-position and a hydroxy or oxo group in the 1-position are analgesic agents and are prepared by treating the corresponding 1 Beta -hydroxy-6cyano compound with a Grignard-type reagent. Typical embodiments are 1 Beta -hydroxy-3-methyl-6-acetyl-1,2,3,4,5,6-hexahydro-2,6methano-3-benzazocine and 3,11 Beta -dimethyl-6-propionyl-1 Beta -hydroxy-8-methoxy-1,2,3,4,5,6-hexahydro-2,6-methano-3benzazocines.

I Unite States atent Block et al.

[ Aug. 29, 1972 Schroder, 790 Bronx River Road, Bronxville, NY. 10708[22] Filed: March 11, 1971 [21] Appl. No.: 123,407

[52] US. Cl ..260/293.54, 424/267 [51] Int. Cl. ..C07d 39/00 [58] Fieldof Search ..260/293.54, DIG. 13

[56] References Cited UNITED STATES PATENTS 3,639,407 2/ 1972 Clarke etal. ..260/293.54

Primary ExaminerHenry R. Jiles Assistant Examiner-G. ThomasAttorney-Karl F. Jorda [57] ABSTRACT 1,2,3 ,4,5,6-Hexahydro-2,6-methano-3 -benzazocines characterized by the presenceof an alkanoyl or benzoyl group in the 6-position and a hydroxy or oxogroup in the 1-position are analgesic agents and are prepared bytreating the corresponding 1 B-hydroxy-6- cyano compound with aGrignard-type reagent. Typical embodiments are1B-hydroxy-3-methyl-6-acetyl- 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine and 3 ,1 1B-dimethyl-6-propionyll B-hydroxy-8- methoxy-l ,2,3,4,5,6-hexahydro-2,6-methano-3- benzazocines.

20 Claims, No Drawings 1 -OXYGENATED-6-ACYL- 1 ,2,3 ,4,5 ,6-HEXAHYDROQ,6-METHANO-3-BENZAZQCINES DETAILED DESCRIPTION This inventionpertains to a class of organic compounds which can be diagrammaticallydepicted by the following structural formula:

(lower)alkoxy, or

and their salts, and to processes and chemical inter-' mediates employedin their preparation.

By the term (lower)alkanoyl is intended the acyl radical of straight andbranched chain alkanoic acids having from 2 to 6 carbon atoms.

By the term (lower)alkoxy is intended a monovalent branched or straighthydrocarbon chain containing from I to 6 carbon atoms and joined throughan oxygen ether bond, such as methoxy, ethoxy, isopropoxy, butoxy andthe like.

These compounds are prepared by treatment of a I B- hydroxy-6-cyanocompound of Formula II with a Grignard-type reagent, especiallyalkyllithium or phenyllithium, with subsequent oxidation, if desired, ofthe resulting lB-hydroxy--acylbenzazocine to the corresponding l-oxocompound. This transformation can be represented as follows:

i NEG R4...

rum

011R N CH3 GHR 110 H0:

li l u RA-C OER: I ICHa In the foregoing, R is hydrogen or (lower)alkoxyand R and R are as previously defined. The compounds of Formula I whereR is hydroxy are obtained by cleavage of a compound of Formula IV whereR is alkoxy, preferably methoxy, with a hydrohalic acid such ashydrobromic or hydriodic acid, with subsequent optional reduction of theketo group in the 1- position to yield the l [3,8-dihydroxy compound.

The compounds of Formula I wherein R is hydrogen are obtained throughthe action of cyanogen bromide followed by treatment with acid.

The compounds of the present invention exist as optical isomers and boththe racemate of these isomers and the individual isomers themselves arewithin the scope of the present invention. The racemate can be separatedinto its individual isomers through the wellknown technique of formationof diastereoisomeric salts with optically active acids, such as dorl-tartaric acid. Alternatively, the individual isomers of the startingmaterials of Formula II can be obtained through resolution of theracemic starting materials and these isomers then subjected to thedescribed procedures to yield the corresponding isomeric finalcompounds.

The starting materials of Formula II are obtained through cyclization ofa quaternary salt of a l-oxo-4- cyano-'4-( 2-dimethylaminoethyl )-l ,2,3,4- tetrahydronaphthylene in the presence of base followed by conversionto the free base.

One important embodiment of the present invention, particularly forpreparing solid pharmaceutical fonnulations is the pharmaceuticallyacceptable non-toxic acid addition salts of these l-oxo andl-hydroxy-6-acyll ,2,3 ,4,5 ,6-hexahydro-2,6-methano-3-benzazocines.Such pharmaceutically acceptable non-toxic salts include those derivedfrom both organic and inorganic acids such as, without limitation,hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic,acetic, lactic, succinic, malic, maleic, aconitic, phthalic, tartaric,embonic, enanthic and like acids.

The compounds defined by Formula I are analgesic agents and thus usefulin the alleviation of pain. As with any analgesic agent the dose must beindividually titrated to the recipient, taking into consideration theseverity of the pain, his overall physical condition and age, and theresponse observed. In recognized pharmacological tests, such as, thetail flick test, the phenylquinone writhing test and the acetic acidstretch test, analgesic activity can generically be observed at levelsfrom 0.5 to 20 mg/kg.

The l-oxo and l-hydroxy-o-acyl-l,2,3,4,5,6-hexahydro-2,6-methano-3-ben2azocines of the present invention are administeredparenterally or orally to achieve an analgesic effect, in any of theusual pharmaceutical forms. These include solid and liquid unit oraldosage forms such as tablets, capsules, powders, suspensions, solutions,syrups and the like, including sustained release preparations, and fluidinjectable forms such as sterile solutions and suspensions The termdosage form as used in this specification and the claims refer tophysically discrete units to be administered in single or multipledosage to animals, each unit containing a predetermined quantity ofactive material in association with the required diluent, carrier orvehicle. The quantity of active material is that calculated to producethe desired therapeutic effect upon administration of one or more ofsuch units.

Powders are prepared by comminuting the l-oxo and l-hydroxy-6 acyl-1,2,3 ,4,5 ,6-hexahydro-2,6-methano- 3-benzazocines to a suitable finesize and mixing with a similarly comminuted diluent pharmaceuticalcarrier such as an edible carbohydrate material as for example, starch.Sweetening, flavoring, preservative, dispersing and coloring agents canalso be present.

Capsules are made by preparing a powder mixture as described above andfilling formed gelatin sheaths. A lubricant such as talc, magnesiumstearate and calcium stearate can be added to the powder mixture as anadjuvant before the filling operation; a glidant such as colloidalsilica may be added to improve flow properties; a disintegrating orsolubilizing agent may be added to improve the availability of themedicament when the capsule is ingested.

Tablets are made by preparing a powder mixture, granulating or slugging,adding a lubricant and disintegrant and pressing into tablets. A powdermixture is prepared by mixing the compound, suitably comminuted, with adiluent or base such as starch, sucrose, kaolin, dicalcium phosphate andthe like. The powder mixture can be granulated by wetting with a bindersuch as syrup, starch paste, acacia mucilage or solutions of cellulosicor polymeric materials and forcing through a screen. As an alternativeto granulating, the powder mixture can be run through the tablet machineand the resulting imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Themedicaments can also be combined with free flowing inert carriers andcompressed into tablets directly without going through the granulatingor slugging steps. A protective coating consisting of a sealing coat ofshe]- lac, a coating of sugar or polymeric material and a polish coatingof wax can be provided. Dyestuffs can be added to these coatings todistinguish different unit dosages.

Oral fluids such as syrups and elixirs can be prepared in unit dosageform so that a given quantity, e.g., a teaspoonful, contains apredetermined amount of the compound. Syrups can be prepared bydissolving the compound in a suitably flavored aqueous sucrose solutionwhile elixirs are prepared through the use of a nontoxic alcoholicvehicle. Suspensions can be formulated by dispersing the compound in anon-toxic vehicle in which it is insoluble.

Fluid unit dosage forms for parenteral administration can be prepared bysuspending or dissolving a measured amount of the compound in anon-toxic liquid vehicle suitable for injection such as an aqueous oroleaginous medium and sterilizing the suspension or solution.Alternatively a measured amount of the compound is placed in a vial andthe vial and its contents are sterilized and sealed. An accompanyingvial or vehicle can be provided for mixing prior to administratron.

The following examples set forth the manner and process of makingtypical embodiments of the invention, without being a limitationthereof, and include the best mode contemplated for carrying out theinvention.

PREPARATION A. To a slurry of 39.4 g of powdered potassium hydroxide,7.0 ml of water and 100 ml of benzene are added 101.0 g of2-chloro-N,N-dimethylethylamine hydrochloride and 50 ml of benzene withrapid stirring.

After thirty minutes, the benzene layer is separated and dried overmagnesium sulfate.

Simultaneously, a slurry of 16.4 g of 58.6% sodium hydride (0.4 M) in 80ml of dimethylsulfoxide is heated under nitrogen for one hour at 60 C.The mixture is cooled and 58.8 g of m-methoxybenzyl nitrile (0.4 M)

are added dropwise over fifteen minutes. The solution is re-cooled andthe dried benzene solution is added dropwise, maintaining thetemperature below 40 C The resultant solution is then heated at 80 C for1 hour, cooled and cautiously treated with 500 ml of water. The aqueouslayer is separated and extracted with benzene, these extracts beingcombined with the initial benzene phase, which is then extracted with 1Nhydrochloric acid. These acidic extracts are rendered basic with 2Nsodium hydroxide and extracted with ether to yield a yellow oil which isdistilled at 1 19-l 22 C/0.03 mm to yield a-(Z-dimethylamino ethyl)-3-methoxyphenylaceto-nitrile.

To a stirred solution of 545 g of this nitrile in 1200 ml of benzene areadded 22.0 g of sodium methoxide. The

resultant slurry is-stirred one hour, after which time 216.0 g (2.5 M)of methyl acrylate in ml of benzene are added at such a rate as tomaintain the termperature between 25 and 30 C.

After stirring overnight, the mixture is poured into 1,400 ml of waterand extracted with ether to yield, upon drying and evaporation, methyl4-cyano-6- dimethylamino-4-( 3-methoxyphenyl)hexanoate.

To a stirred solution of 35 g of potassium hydroxide in 200 ml ofmethanol are added g of this ester in 200 ml of methanol at such a rateas to maintain the temperature below 15 C. Stirring is continued for 5hours, after which time the mixture is concentrated to dryness. Theresidual material is slurn'ed several times with toluene andconcentrated to dryness to remove traces of methanol. The residue istreated with water and again concentrated to dryness. The resultantmaterial is dissolved in water and washed with ether (recoveringstarting amine) and the aqueous phase is rendered acidic withconcentrated hydrochloric acid and evaporated to dryness. Triturationwith acetone precipitates potassium chloride, which is removed byfiltration. Evaporation of the filtrate yields the product as an oilwhich crystallizes upon addition of acetone. Recrystallization fromisopropanol then produces 4- cyano-4-( 3-methoxyphenyl)-6-dimethylaminohexanoic acid, m.p. 181183 C.

B. A mixture of 3.26 g of4-cyano-4-(3-methoxyphenyl)-6-dimethylaminohexanoic acid and 15.0 ml ofthionyl chloride are heated at reflux for thirty minutes. The resultantsolution is concentrated to dryness and treated once with ethylenedichloride followed by evaporation to remove excess thionyl chloride.The resultant red viscous material is dissolved in 8.0 ml of ethylenedichloride with heating, cooled slightly, and treated with 10.0 ml ofcarbon disulfide, maintaining a temperature of approximately 30 C. Asthe mixture is cooled, an insoluble gummy material begins to form, atwhich time 4.4 g of aluminum chloride is mmediately added. Sufficientcooling should be present since a violent exotherrn ensues as thealuminum chloride is added.

The reaction mixture is heated to reflux for fifteen minutes, cooled andthe reddish mother liquor decanted to leave an insoluble complex. Thedecanted residue is dissolved in water and washed with ether. Theresultant aqueous phase is rendered basic with concentrated ammoniumhydroxide and extracted with ether to yield an oil upon evaporation.This oil is dissolved in acetone and rendered acidic with 30% hydrogenbromide in acetic acid The precipitated product is collected byfiltration and recrystallized from methanol to yield 1-oxo-4-cyano-4-(2-dimethylaminoethyl)-6-methoxy- 1 ,2,3 ,4,-tetrahydronapthalenehydrobromide, m.p. 236-238 C.

In a similar fashion is obtained 1-oxo-4-cyano-4-(2- dimethylaminoethyl1 ,2,3 ,4-tetrahydronaptha-lene hydrobromide, m.p. 219.

C. To a refluxing solution of 3.54 g (0.01M) of 1-oxo4-cyano-4-(Z-dimethylaminoethyl)-6-methoxy-1,2,3,4-tetrahydronaphthalene hydrobromide and ml of acetic acid isadded, over 15 minutes, 1.76 g (0.011M) of bromine in 9 ml of aceticacid. The solution is heated at reflux for an additional 15 minutes,cooled, and then concentrated to dryness. Trituration of the residuewith acetone yields crude 1-oxo-2-bromo-4-cyano-4-(2-dimethylaminoethyl)6-methoxy-1,2,3,4-tetrahydronaphthalene hydrobromide, m.p. 205-10bL C.

To a well stirred suspension of 3.25 g (7.5mMole) of this hydrobromideand 12.0 ml of water is added dropwise 1.30 ml of concentrated ammoniumhydroxide with cooling. After stirring for 1 hour, the slurry isfiltered to yield 1-oxo-3-methyl-6-cyano-8-methoxy- 1 ,2,3 ,4,5,6-hexahydro-2,6-methano-3-benzazocine methobromide, m.p. 245250 C.Additional product is isolated by concentrating the mother liquor todryness and triturating with a mixture of ethanol-acetone.

A suspension of 9.0 ml of l-nonanol and 1.75 g (5 mMole) of thismethobromide is immersed in a bath preheated to 240 C. After refluxingminutes, the solution is cooled and diluted with ether. The solid whichforms is collected and recrystallized from tetrahydrofuran to yield1-oxo-3-methyl-6-cyano-8- methoxy- 1 ,2,3 ,4,5,6-hexahydro-2,6-methano-3- benzazocine, m.p. 163165 C.

Similarly obtained is 1-oxo-3-methyl-6-cyano- 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine, m.p. 102103 C.

D. To 8.0 g (31.2 mM) of 1-oxo-3-methyl-6-cyano-8- methoxy- 1 ,2,3 ,4,5,6-hexahydro-2,6-methano*3- benzazocine in 300 ml methanol is added 1.8g of sodium borohydride which results in gas evolution and a slightexotherm. The solution is stirred at room temperature for four hours.The methanol is then removed under vacuum and the residue is dissolvedin 1:1 chloroforrmether. The organic phase is washed with water untilthe washings are neutral, dried, and evaporated to dryness to yield anoil. The oil is slurried in 100 ml of cyclohexane and scratched.Immediate crystallization should occur. The resultant solid isseparated, dried and recrystallized from isopropanol to yield 1B-hydroxy-3-methyl-6-cyano-8-methoxyl ,2,3 ,4,5,6-hexahydro-2,6-methano-3-benzazocine, m.p. 117120 C.

Similarly obtained is 1B-hydroxy-3-methyl-6-cyano- 1 ,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine, m.p. 114 C.

By following similar procedures to those herein described, but utilizingmethyl crotonate in place of methyl acrylate in part (A) there isobtained 13- hydroxy-3, 1 1 B-dimethyl-6-cyano-8-methoxy- 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine, m.p. 252-254 C as thehydrochloride salt.

EXAMPLE 1 To a solution of 20.0 g of 1B-hydroxy-3-methyl-6- cyano-l ,2,3,4,5 ,6-hexahydro-2,6-methano-3- benzazocine in 250 ml of drytetrahydrofuran under a nitrogen atmosphere are added dropwise withexternal cooling, ml of a 1.62 molar ethereal methyllithium solution.One hundred and fifty milliliters of tetrahydrofuran are then added andthe mixture is heated with distillation of the solvent until an internaltemperature of 66 C is attained. During this time approximately 170 rnlof solvent are obtained. The mixture is then heated at reflux undernitrogen for 3 hours, cooled and treated with concentrated hydrochloricacid until foaming ceases. The remaining solvent is removed byevaporation and the residue is treated with 300 ml of 2N hydrochloricacid and heated at reflux for 30 minutes. The reaction mixture is thencooled, rendered basic and extracted with ether. The ethereal extractsare dried and evaporated and the residual oil is treated with 50 ml ofether. The solid remaining is collected and recrystallized fromcyclohexane to yield 18- hydroxy-3-methyl-6-acetyl-l ,2,3 ,4,5,6-hexahydro-2,6- methano-3-benzazocine, m.p. 98.0-99.5 C. A typicalcarbon-hydrogen analysis is as follows:

Calc. C,,H,,NO Found:

By utilizing the individual dand l-isomers of the starting compound, thecorresponding dand l-isomers of the final compound are obtained, m.p.s 1101 12 C; optical rotation as follows:

A d 1 [al (c=l.04) (c=l.05)

EXAMPLE 2 To 3.50 g of1B-hydroxy-3-methyl-6-cyanol,2,3,4,5,6-hexahydro-2,6-methano-3benzazocinein ml of dry tetrahydrofuran under a nitrogen atmosphere are added 42.3ml of a 0.8 molar ethereal ethyllithium solution. The mixture isrefluxed under a nitrogen atmosphere for 3 hours. The cooled mixture isrendered acidic with 2N hydrochloric acid and refluxed for 15 minutes.The tetrahydrofuran is removed under vacuum and the residue is dilutedwith water. The aqueous mixture is rendered basic with ammoniumhydroxide and extracted with chloroform. The chloroform extracts arewashed with water and dried over magnesium sulfate. The drying agent isremoved by filtration and the chloroform is evaporated to yield and oilwhich crystallizes. The solid is collected and recrystallized severaltimes from cyclohexane to yield 1 B-hydroxy-3-methyl-6-propionyl-1 ,2,3,4,5 ,6-hexahydro-2,6-methano-3-benzazocine, m.p. l l8l20 C.

In a similar fashion, utilizing an equivalent amount of l B-hydroxy-3-methyl-6-cyano-8-methoxy-l ,2,3 ,4,5 ,6-hexahydro-2,6-methano-3-benzazocine, there is obtained1B-hydroxy-3-methyl-6-propionyl-8-methoxyl ,2,3 ,4,5,6-hexahydro-2,6-methano-3-benzazocine, m.p. 143145 C.

EXAMPLE 3 lB-Hydroxy-3 -methyl-6-cyano- 1 ,2,3 ,4,5,6-hexahydro-2,6-methano-3-benzazocine is treated in the mannerdescribed in Examples 1 and 2 with (a) isopropyl-lithium, (b)nbutyllithium and (C) phenyllithium to respectively yield a. 1B-Hydroxy-3-methyl-6-( 2-methylpropionyl l ,2,3 ,4,5,6-hexahydro-2,6-methano-3-benzazocine, m.p. 25 8-259 C;

b. 1 B-hydroxy-3-methyl-6-pentanoyl- 1 ,2,3 ,4,5 ,6-hexahydro-2,6-methano-3-benzazocine, m.p. as the hydro-bromide salt 19l193 C; and

c. l B-hydroxy-B-methyl-6-benzoyl- 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine, m.p. 152l53 C EXAMPLE 4A solution of 1.75 g (7.14 mM) OF 1B-hydroxy-3- methyl-6-acetyll ,2,3,4,5 ,6-hexahydro-2,6-methano-3- benzazocine in 35 ml of aceticanhydrlde is allowed to stand at room temperature for 2 days. The excessacetic anhydride is then removed under vacuum and the residue is treatedwith water. The pH is adjusted to 9 with dilute base and a white solidimmediately precipitates. The solid is collected by filtration, driedand recrystallized from isopropanol to yield 1B-acetoxy-3-methyl-6-acetyl-l ,2,3 ,4,5 ,6-hexahydro-2,6-methano-S-benzazocine, m.p. l42143 C.

In a similar fashion are obtained 1Bacetoxy-3- methyl-6-propionyl-l ,2,3,4,5 ,6-hexahydro-2,6- methano-3-ben2azocine, m.p. 133l34 C and 1B-acetoxy-3-methyl-6-propionyl-8-methoxy-l ,2,3 ,4,5 ,6-hexahydro-2,6-methano-3-benzazocine, m.p. l461 48 C.

EXAMPLE A solution of 0.45 g of lB-acetoxy-3-methyl-6- propionyl- 1 ,2,3,4,5,6,6-hexahydro-2,6-methano-3- benzazocine in 60 ml of chloroform isadded dropwise to a mixture of 0.19 g of cyanogen bromide in 80 ml ofchloroform. The mixture is stirred for 1 hour at room temperature andthen for 4 hours at reflux. The solvent is then removed by evaporationunder vacuum and the residue is taken up in chloroform. The solution iswashed with 2N hydrochloric acid and dried over sodium sulfate. Uponevaporation of the dried solution, there is obtainedlB-acetyl-3-cyano-6-propionyl- 1 ,2,3,4,5,6,-hexahydro-2,6-methano-3-benzazocine which can be used in thefollowing step without further purification.

A mixture of 0.31 g of this cyano compound, 30 ml of ethanol and 50 mlof 2N hydrochloric acid is refluxed for 4 hours. The solvent is thenremoved by evaporation and the residue is rendered basic with ammoniumhydroxide and extracted with chloroform. These extracts are dried andevaporated to yield an oil which is heated at reflux with 50 ml of 2Nhydrochloric acid for 3 hours. The reaction product is cooled, washedwith chloroform, rendered basic with ammonium hydroxide and extractedwith chloroform. Evaporation of these extracts yieldslfl-hydroxy-o-propionyll,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocineas an oil.

EXAMPLE 6 1 ,B-Hydroxy-3 -methyl-6-propionyl- 8-methoxy-1,2,3,4,5,6-hexahydro-2,6-methano-I i-benzazocine is treated withchromium trioxide-sulfuric acid reagent for 15 minutes. Uponneutralization and extraction with chlorofomi, there is obtainedl-oxo-3-methyl-6- propionyl-8-methoxy-1 ,2,3,4,5 ,6-hexahydro-2,6-methano-3-benzazocine, m.p. 134136 C.

In a similar fashion 1B-hydroxy-6-propionyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine is converted tol-oxo-6-propionyll ,2,3,4,5 ,6-hexahydro- 2,6-methano-3-benzazocine,m.p. as the hydrochloride salt 227229 C.

EXAMPLE 7 A mixture of 0.46 g of l-oxo-3-methyl-6-propionyl- 8-methoxy-l,2,3,4,5 ,6-hexahydro-2,6-methano-3- benzazocine and 12 ml of hydriodicacid are refluxed for minutes. The mixture is poured into 15 ml of waterand 15 ml of ammonium hydroxide and washed with the chloroform. Theaqueous residue is reduced to one half its original volume and adjustedto pH 7. The solid which forms is collected and dried to yield l-oxo-3-methyl-6-propionyl-8-hydroxy-1 ,2,3 ,4,5,6-hexahydro-2,6-methano-3-benzazocine, m.p. 230232 C.

EXAMPLE 8 To 1.05 g of1-oxo-6-propionyl-l,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine (seeExample 6) in 40 ml DMF was added 0.61 g of N,N- diisopropylethylaminean 0.71 g of 1-bromo-3-methyl- Z-butene. The mixture was heated at for 1hour and stirred overnight at room temperature. DMF was removed undervacuum. The residue was taken up in ether an d the ether was washed withwater. The ether was dried, evaporated, yielding 1.14 g of an oil. Theoil was dissolved in 10 ml of lPA, made acidic with Et O/HC1, cooled andfiltered. The solid was washed with Et O and dried, yielding 1.00 g(67%) of white solid m.p. 2l5218.

EXAMPLE 9 The free base from 1.30 g of l-oxo- O-dimethyl-allyl-6-propionyl-l ,2,3 ,4,5 ,6-hexahydro-2,6-methano-3- benzazocine wasdissolved in 50 ml of abs. EtOh and was treated with 7.2 ml ofNaBI-h/EtOI-l (calc. 0.52 mM) and dried at room temperature for hours.The solvent was removed, and the residue dissolved in CHCl and washedwith water, dried and evaporated,

yielding an oil. The residue was dissolved in ml of 5 EtOAc, made acidicwith Et O/HCI and heated. After adding several drops of IPA, aprecipitate formed. This was filtered and dried, yielding b 0.20 g (15%)of white solid, mp. 197-200.

What is claimed is:

CHRK

where R is oxygen, [a-hydrogen,B-hydroxy], or [ahydro gen ,B-( lower)alkanoyloxy R is hydrogen, methyl or dimethylallyl R is hydrogen ormethyl;

R is (lower)alkyl orphenyl; and

R is hydrogen, hydroxy,

(lower)alkanoyloxy.

2. The pharmaceutically acceptable non-toxic acid addition salts of acompound according to claim 1.

(lower)alkoxy, or

3. A compound according to claim 1 wherein R is I 7. The compoundaccording to claim 1 which is 13- hydroxy-3-methyl-6 2-methylpropionyl l,2,3 ,4,5 ,6- hexahydro-2,6-methano-3-benzazocine.

9. The compound according to claim 1 which is 113hydroxy-3-methyl-6-pentanoyl-l ,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine.

10. The compound according to claim 1 which is 15-hydroxy-3-methyl-6-benzoyl-1 ,2,3 ,4,5 ,6-hexahydro-2,6-methano-3-benzazocine.

11. The compound according to claim 1 which is 13-acetoXy-3-methyl-6-acetyl-1 ,2,3,4,5 ,6-hexahydro-2,6-methano-3-benzazocine.

12. The compound according to claim 1 which is 13-acetoxy-3-methyl-6-propionyl-l ,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine.

13. The compound according to claim 1 which is 16- acetoxy-3-methyl-6-propionyl-8-methoxy-l ,2,3 ,4,5,6-hexahydro-Z,6-methano-3-benzazocine.

14. The compound according to claim 1 which is 16-hydroxy-fi-propionyl-l ,2,3 ,4,5 ,6-hexahydro-2,6-methano-3-benzazocine.

15. The compound according to claim 1 which is l-0xo-3-methyl-6Propionyl-8-methoxyl,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine.

16. The compound according to claim 1 which is 1- oxo-3-methyl-6-propionyl- 1 ,2,3 ,4,5 ,6-hexahydro-2,6-

' methano-3-benzazocine;

17. The compound according to claim 1 which is 1-oxo-3-methyl-6propionyl-8-hydroxy-l ,2,3 ,4,5,6-hexahydro-2,6-methano-3-benz .ocine.

8. The compound accor mg to claim 1 which is l- UNITED STATES PATENTOFFICE CERTIFICATE OF CORRECTION Patent No. 3 687, 957 Dated August 29,1972 Inventor(s) Fred B. Block et al It is certified that error appearsin the above-identified patent and that said Letters Patent are herebycorrected as shown below:

Column 9, above the structural formula insert l, A

compound of the formula Column 10, insert the following claim:

7. The compound according to claim 1 which is 16- hydroxy3-methyl6-propionyl-8-methoxy-l,2,3, l,5,6-hexahydro-2,6methano-3-benzazocine.

Column 10, line 1, delete "7" and substitute 8 Signed and sealed this10th day of September 197 (SEAL) Attest:

McCOY M. GIBSON, JR. Ca MARSHALL DANN Attesting Officer Commissioner ofPatents aaa

2. The pharmaceutically acceptable non-toxic acid addition salts of acompound according to claim
 1. 3. A compound according to claim 1wherein R1 is ( Alpha -hydrogen, Beta -hydroxy), R2 is methyl, R3 ishydrogen and R5 is hydrogen or methoxy.
 4. The compound according toclaim 1 which is 1 Beta-hydroxy-3-methyl-6-acetyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine.5. The compound according to claim 1 which is 1 Beta-hydroxy-3-methyl-6-acetyl-8-methoxy-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine.
 6. The compound according to claim 1 which is 1 Beta-hydroxy-3-methyl-6-propionyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine.
 7. The compound according to claim 1 which is 1 Beta-hydroxy-3-methyl-6-propionyl-8-methoxy-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine.
 8. The compound according to claim 1 which is 1 Beta-hydroxy-3-methyl-6-(2-methylpropionyl)-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine.
 9. The compound according to claim 1 which is 1 Beta-hydroxy-3-methyl-6-pentanoyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine.
 10. The compound according to claim 1 which is 1 Beta-hydroxy-3-methyl-6-benzoyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine.11. The compound according to claim 1 which is 1 Beta-acetoxy-3-methyl-6-acetyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine.12. The compound according to claim 1 which is 1 Beta-acetoxy-3-methyl-6-propionyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine.
 13. The compound according to claim 1 which is 1 Beta-acetoxy-3-methyl-6-propionyl-8-methoxy-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine.
 14. The compound according to claim 1 which is 1 Beta-hydroxy-6-propionyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine.15. The compound according to claim 1 which is1-oxo-3-methyl-6-propionyl-8-methoxy-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine.
 16. The compound according to claim 1 which is1-oxo-3-methyl-6-propionyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine.17. The compound according to claim 1 which is1-oxo-3-methyl-6-propionyl-8-hydroxy-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine.
 18. The compound according to claim 1 which is1-oxo-3-dimethylallyl-6-propionyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine.
 19. The compound according to claim 1 which is 1 Beta-hydroxy-3-dimethylallyl-6-propionyl-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine.
 20. The compound according to claim 1 which is 3,11 Beta-dimethyl-6-propionyl-1 Beta-hydroxy-8-methoxy-1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine.